Novel epigenetic molecular therapies for imprinting disorders

Wang, Sung Eun; Jiang, Yong-hui

doi:10.1038/s41380-023-02208-7

Cited by 8 publications

(2 citation statements)

References 156 publications

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“…ASO enables the Ube3a-ATS inhibition or inactivation, resulting in rescuing neurobehavioral and neuropsychological impairments. These can also be achieved by CRISPR/ Cas9 genome editing or CRISPRmediated RNA editing (Wang and Jiang 2023;Wolter et al 2020;Schmid et al 2021). Importantly, various ASO designs are being tested in 4 active phase 1/ 2a clinical trials (NCT05127226, NCT04428281, and NCT04259281).…”

Section: Treatment Optionsmentioning

confidence: 99%

Chromatinopathies: insight in clinical aspects and underlying epigenetic changes

Bukowska-Olech,

Majchrzak-Celińska,

Przyborska

et al. 2024

J Appl Genetics

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Chromatinopathies (CPs), a group of rare inborn defects characterized by chromatin state imbalance, have evolved from initially resembling Cornelia de Lange syndrome to encompass a wide array of genetic diseases with diverse clinical presentations. The CPs classification now includes human developmental disorders caused by germline mutations in epigenes, genes that regulate the epigenome. Recent advances in next-generation sequencing have enabled the association of 154 epigenes with CPs, revealing distinctive DNA methylation patterns known as episignatures.It has been shown that episignatures are unique for a particular CP or share similarities among specific CP subgroup. Consequently, these episignatures have emerged as promising biomarkers for diagnosing and treating CPs, differentiating subtypes, evaluating variants of unknown significance, and facilitating targeted therapies tailored to the underlying epigenetic dysregulation.The following review was conducted to collect, summarize, and analyze data regarding CPs in such aspects as clinical evaluation encompassing long-term patient care, underlying epigenetic changes, and innovative molecular and bioinformatic methodologies that have been devised for the assessment of CPs. We have also shed light on promising novel treatment options that have surfaced in recent research and presented a synthesis of ongoing clinical trials, contributing to the current understanding of the dynamic and evolving nature of CPs investigation.

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Section: Treatment Optionsmentioning

confidence: 99%

Chromatinopathies: insight in clinical aspects and underlying epigenetic changes

Bukowska-Olech,

Majchrzak-Celińska,

Przyborska

et al. 2024

J Appl Genetics

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“…Since the discovery of genomic imprinting 3,4 , investigations have focused on two fundamental questions: how cells recognize the paternal and maternal alleles and how cells maintain allele-specific repression of imprinted genes. The imprinting domain of chromosome 15q11.2-q13, implicated in the pathogenesis of both Prader-Willi syndrome (PWS) and Angelman syndrome (AS), has long been an established model for investigating genomic imprinting [5][6][7] . The 15q11-q13 imprinting domain contains a PWS imprinting center (PWS-IC) and a AS-imprinting center (AS-IC) and two functionally distinct and oppositely imprinted regions [8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

Mechanism of EHMT2-mediated genomic imprinting associated with Prader-Willi syndrome

Jiang,

Wang,

Cheng

et al. 2024

Preprint

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Prader-Willi Syndrome (PWS) is caused by loss of expression of paternally expressed genes in the human 15q11.2-q13 imprinting domain. A set of imprinted genes that are active on the paternal but silenced on the maternal chromosome are intricately regulated by a bipartite imprinting center (PWS-IC) located in the PWS imprinting domain. In past work, we discovered that euchromatic histone lysine N-methyltransferase-2 (EHMT2/G9a) inhibitors were capable of un-silencing PWS-associated genes by restoring their expression from the maternal chromosome. Here, in mice lacking the Ehmt2 gene, we document unsilencing of the imprinted Snrpn/Snhg14 gene on the maternal chromosome in the late embryonic and postnatal brain. Using PWS and Angelman syndrome patient derived cells with either paternal or maternal deletion of 15q11-q13, we have found that chromatin of maternal PWS-IC is closed and has compact 3D folding confirmation. We further show that a new and distinct noncoding RNA preferentially transcribed from upstream of the PWS-IC interacts with EHMT2 and forms a heterochromatin complex to silence gene expression of SNRPN in CIS on maternal chromosome. Taken together, these findings demonstrate that allele-specific recruitment of EHMT2 is required to maintain the maternal imprints. Our findings provide novel mechanistic insights and support a new model for imprinting maintenance of the PWS imprinted domain.

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Novel therapeutic agents in clinical trials: emerging approaches in cancer therapy

Joshi,

Sharma,

Prasad

et al. 2024

Discov Onc

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Novel therapeutic agents in clinical trials offer a paradigm shift in the approach to battling this prevalent and destructive disease, and the area of cancer therapy is on the precipice of a trans formative revolution. Despite the importance of tried-and-true cancer treatments like surgery, radiation, and chemotherapy, the disease continues to evolve and adapt, making new, more potent methods necessary. The field of cancer therapy is currently witnessing the emergence of a wide range of innovative approaches. Immunotherapy, including checkpoint inhibitors, CAR-T cell treatment, and cancer vaccines, utilizes the host’s immune system to selectively target and eradicate malignant cells while minimizing harm to normal tissue. The development of targeted medicines like kinase inhibitors and monoclonal antibodies has allowed for more targeted and less harmful approaches to treating cancer. With the help of genomics and molecular profiling, “precision medicine” customizes therapies to each patient’s unique genetic makeup to maximize therapeutic efficacy while minimizing unwanted side effects. Epigenetic therapies, metabolic interventions, radio-pharmaceuticals, and an increasing emphasis on combination therapy with synergistic effects further broaden the therapeutic landscape. Multiple-stage clinical trials are essential for determining the safety and efficacy of these novel drugs, allowing patients to gain access to novel treatments while also furthering scientific understanding. The future of cancer therapy is rife with promise, as the integration of artificial intelligence and big data has the potential to revolutionize early detection and prevention. Collaboration among researchers, and healthcare providers, and the active involvement of patients remain the bedrock of the ongoing battle against cancer. In conclusion, the dynamic and evolving landscape of cancer therapy provides hope for improved treatment outcomes, emphasizing a patient-centered, data-driven, and ethically grounded approach as we collectively strive towards a cancer-free world.

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Novel epigenetic molecular therapies for imprinting disorders

Cited by 8 publications

References 156 publications

Chromatinopathies: insight in clinical aspects and underlying epigenetic changes

Chromatinopathies: insight in clinical aspects and underlying epigenetic changes

Mechanism of EHMT2-mediated genomic imprinting associated with Prader-Willi syndrome

Novel therapeutic agents in clinical trials: emerging approaches in cancer therapy

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